Actionable Exomic Secondary Findings in 280 Lebanese Participants

Abstract

The expanded use of NGS tests in genetic diagnosis enables the massive generation of data related to each individual, among which some findings are of medical value. Over the last three and a half years, 280 unrelated Lebanese patients, presenting a wide spectrum of genetic disorders were referred to our center for genetic evaluation by WES. Molecular diagnosis was established in 56% of the cases, as was previously reported. The current study evaluates secondary findings in these patients in 59 genes, linked to conditions mostly responsive to medical interventions, as per the ACMG guidelines. Our analysis allowed us to detect 19 pathogenic/likely pathogenic variants in 24 individuals from our cohort. Dominant actionable variants were found in 17 individuals representing 6% of the studied population. Genes associated with dominant cardiac diseases were the most frequently mutated: variants were found in 2.1% of our cohort. Genetic predisposition to cancer syndromes was observed in 1.07% of the cases. In parallel to dominant disease alleles, our analysis identified a recessive pathogenic disease allele in 2.5% of the individuals included in this study. Of interest, some variants were detected in different patients from our cohort thus urging the study of their prevalence in our population and the implementation, when needed, of specific genetic testing in the neonatal screening panel. In conclusion, here we report the first study estimating the actionable pathogenic variant load in the Lebanese population. Communicating current findings to the patients will enable them to benefit from a multi-disciplinary approach. Furthermore, tailoring the ACMG guidelines to the population is suggested, especially in highly consanguineous populations where the information related to recessive alleles might be highly beneficial to patients and their families.

Frequency and management of medically actionable incidental findings from genome and exome sequencing data: a systematic review

“…Different ancestries were found in the 20 included studies. The majority 122 of the studies were conducted in populations from European, African American, and Asian 123 ancestries, while two studies assessed the frequency of incidental findings in the Arabic 124 population (23,25).…”

“…Eight studies analyzed the frequency of incidental findings in a cohort with a single ancestry or ethinic group such as, South Korean, East Asian, Caucasian, European, Lebanese, Taiwanese, Qatari, and Dutch (10, 11,14,16,20,23,25,43). An additional four studies reported the frequency of incidental findings in their cohorts based on ancestry groups (12,22,41,42), while eight studies did not provide the frequency for sub-populations (Table 3).…”

Secondary findings in a large Pakistani cohort tested with whole genome sequencing

“…The studies with very large sample size can present some hurdles, such as ethical or financial, however, too small sample sized studies may prevent the findings from being extrapolated to population level (Faber and Fonseca 2014). Among the published studies, the highest frequencies of SF, 6.6% and 6.1%, were shown in the studies with relatively low numbers of participants, 196 and 280, respectively (Jang et al 2015;Jalkh et al 2020).…”

“…Most of the SF studies represented local populations including Saudi Arabia (Aloraini et al 2021), China (Chen et al 2018), Qatar (Jain et al 2018;Elfatih et al 2021), Lebanon (Jalkh et al 2020), Korea (Jang et al 2015), Taiwan (Kuo et al 2020), Netherlands (Haer-Wigman et al 2019), Singapore (Jamuar et al 2016), Thailand (Chetruengchai and Shotelersuk 2021). There were more representative studies: with self-reported race/ethnic groups including Hispanic or Latinx, Black or African American, Asian, American Indian, Alaska Native, or Pacific Islander, and White (Gordon 2020); East Asian ancestry (China, Vietnam) (Tang et al 2018), European and African Americans (Natarajan et al 2016); 1000 Genomes project, which includes 14 different populations in 4 major ancestry groups (Europe, East Asia, Africa, and the Americas) (Olfson et al 2015).…”

Secondary findings from whole-exome sequencing data in families with familial combined hyperlipidemia (FCHL)

“…To date, various studies have been performed on a considerable number of samples among different populations, and the data obtained confirm the presence of a change in the number of secondary findings between different groups. For example, Jalkh et al have identified 4262 variants in the 59 selected genes among 280 Lebanese individuals, of which 6% were pathogenic or possibly pathogenic [22]. Xue et al have reported a frequency of 11% of secondary findings among 179 subjects [23], and in the examination of 1,000 WES belonging to Europeans/African people, they have obtained 1.2 to 3.4% of secondary findings [24].…”